NLRP3 inflammasome upregulates PD-L1 expression and contributes to immune suppression in lymphoma
NLRP3 inflammasome upregulates PD-L1 expression and contributes to immune suppression in lymphoma
复制标题
NLRP3 炎性体上调 PD-L1 表达并有助于淋巴瘤的免疫抑制。
DOI：
10.1016/j.canlet.2020.10.024
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发表时间：
2021-01-28
期刊：
影响因子：
9.7
通讯作者：
Ji, Chunyan
中科院分区：
文献类型：
--
作者：
Lu, Fei;Zhao, Yanan;Ji, Chunyan
NLRP 3炎性体在各种恶性肿瘤中起促肿瘤发生作用。然而，其在淋巴瘤发生中的潜在作用仍不清楚。在这项研究中，我们确定了弥漫性大B细胞淋巴瘤（DLBCL）患者的免疫抑制状态，其特征是淋巴瘤组织中白细胞介素（IL）-18水平显著升高，与程序性死亡配体1（PD-L1）表达呈正相关。此外，DLBCL细胞系中的NLRP 3炎性小体激活上调PD-L1并降低细胞毒性T细胞的比例。体内NLRP 3炎性体阻断通过下调肿瘤微环境中的PD-L1和降低表达PD-1/TIM-3的T细胞、髓源性抑制细胞、肿瘤相关巨噬细胞和调节性T细胞的比例来抑制淋巴瘤生长并改善抗肿瘤免疫。进一步的体内研究表明IL-18是参与抗淋巴瘤免疫负调节的主要效应细胞因子。有趣的是，NLRP 3阻断剂与抗PD-L1治疗的组合在淋巴瘤治疗期间发挥了拮抗作用。总之，我们的研究结果表明，NLRP 3炎性小体通过调节PD-L1和免疫细胞促进免疫抑制。因此，本研究强调了NLRP 3炎性小体在淋巴瘤中的预后和治疗价值。
The NLRP3 inflammasome plays a pro-tumorigenic role in various malignancies. However, its potential role in lymphomagenesis remains unclear. In this study, we identified an immunosuppressive state in patients with diffuse large B cell lymphoma (DLBCL), which was characterized by markedly elevated interleukin (IL)-18 levels in lymphoma tissues and positive correlation with programmed death ligand 1 (PD-L1) expression. Furthermore, NLRP3 inflammasome activation in DLBCL cell lines upregulated PD-L1 and reduced the proportion of cytotoxic T cells. NLRP3 inflammasome blockade in vivo suppressed lymphoma growth and ameliorated anti-tumor immunity by downregulating PD-L1 in the tumor microenvironment and decreasing the proportion of PD-1/TIM-3expressing T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Further in vivo studies revealed IL-18 as the main effector cytokine involved in the negative regulation of anti lymphoma immunity. Interestingly, NLRP3 blockers combined with anti-PD-L1 treatment exerted antagonistic effects during lymphoma therapy. Altogether, our findings indicate that NLRP3 inflammasome promotes immunosuppression by modulating PD-L1 and immune cells. Accordingly, this study highlights the prognostic and therapeutic values of the NLRP3 inflammasome in lymphoma.